1. Field of the Invention
This invention relates generally to immediate release fenofibrate dosage forms.
2. Description of Related Art
Fenofibrate is an active principle which is very poorly soluble in water, and the absorption of fenofibrate in the digestive tract is limited. An increase in its solubility leads to better digestive absorption. Various approaches have been explored in order to increase the solubility of fenofibrate, including micronization of the active principle, addition of a surfactant, and comicronization of fenofibrate with a surfactant.
Fenofibrate is freely soluble in methanol and acetonitrile, and insoluble in water. Having no ionizable group, fenofibrate solubility is not influenced by changes in medium pH. However, the aqueous solubility of Fenofibrate can be improved in the presence of surfactants. As the concentration of the surfactant sodium lauryl sulfate, for example, increases from 0.0 M to 0.1M, fenofibrate solubility increases from 0.8 mg/L to 910.8 mg/L.
U.S. Pat. No. 4,800,079 (Jan. 24, 1989, Jean-Francois Boyer) describes a granular medicine based on fenofibrate, each granule comprising an inert core, a layer based on fenofibrate, and a protective layer. The medicine is characterized in that the fenofibrate is present in the form of crystalline microparticles having a size of less than 30 microns, and preferably less than 10 microns. The layer based on fenofibrate includes a binder selected from the group consisting of methacrylic polymers, polyvinylpyrolidone, cellulose derivatives, and polyethylene glycols.
U.S. Pat. No. 7,101,574 (Sep. 5, 2006, Bruno Criere et. al.) describes a pharmaceutical composition containing micronized fenofibrate, a surfactant and a cellulose derivative as a binder, preferably hydroxypropylmethylcellulose. The cellulose derivative represents less than 20 wt. % of the composition, while the fenofibrate is present in an amount greater than or equal to 60% by weight of the pharmaceutical composition. The disclosed formulation provides enhanced bioavailability of the active principle.
EP Patent 0256933 describes fenofibrate granules containing micronized fenofibrate to increase fenofibrate bioavailability. The fenofibrate microparticles are less than 50 micron in size, and polyvinylpyrrolidone is used as a binder. The document describes other types of binder, such as methacrylic polymers, cellulose derivatives and polyethylene glycols.
EP Patent 0330532 describes improving the bioavailability of fenofibrate by comicronizing it with a surfactant, such as sodium lauryl sulfate. The comicronized product is then granulated by wet granulation in order to improve the flow capacities of the powder and to facilitate the transformation into gelatin capsules. This comicronization allows a significant increase in the bioavailability compared to the use of fenofibrate described in EP 0256933. The granules described in EP 0330532 contain polyvinylpyrrolidone as a binder. EP 0330532 teaches that the comicronization of fenofibrate with a solid surfactant improves the bioavailability of fenofibrate compared to either micronized fenofibrate, or to the combination of a surfactant and of micronized fenofibrate. However, the formulation of EP 0330532 is unsatisfactory, as it does not provide complete bioavailability of the active ingredient. The technique of co-micronizing fenofibrate with a solid surfactant improves dissolution of fenofibrate, but still produces incomplete dissolution.